The present invention relates to a genus of substituted oximes and hydrazones useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK1) and/or neurokinin-2 receptor (NK2) and/or neurokinin-3 receptor (NK3).
Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, depression, and various gastrointestinal disorders such as Crohn""s disease.
In particular, NK1 receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK2 receptors have been associated with smooth muscle contraction, making NK1 and NK2 receptor antagonists especially useful in the treatment and prevention of asthma.
Substituted oxime and hydrazone NK1 and NK2 receptor antagonists have previously been disclosed in U.S. Pat. Nos. 5,696,267, 5,688,960, and 5,789,422.
Compounds of the present invention are represented by the formula I 
or a pharmaceutically acceptable salt thereof, wherein:
a is 0, 1, 2 or 3;
b and d are independently 0, 1 or 2;
R is H, C1-6 alkyl, xe2x80x94OR6 or xe2x80x94F;
A is xe2x95x90Nxe2x80x94OR1 or xe2x95x90Nxe2x80x94N(R2)(R3);
when d is not 0, X is a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR9xe2x80x94, xe2x80x94S(O)exe2x80x94, xe2x80x94N(R6)C(O)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)NR6xe2x80x94, xe2x80x94OC(xe2x95x90S)NR6xe2x80x94, xe2x80x94N(R6)C(xe2x95x90S)Oxe2x80x94, xe2x80x94S(O)2N(R6)xe2x80x94, xe2x80x94N(R6)S(O)2xe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94 or xe2x80x94N(R6)C(O)NR7; and
when d is 0, X is a bond or xe2x80x94NR6xe2x80x94;
T is H, R4-aryl, R4-heterocycloalkyl or R4-heteroaryl;
Q is R5-phenyl, R5-naphthyl or R5-heteroaryl;
R1 is H, C1-6 alkyl, xe2x80x94(C(R6)(R7))nxe2x80x94G, xe2x80x94G2, xe2x80x94(C(R6)(R7))pxe2x80x94Mxe2x80x94(C(R13)(R14))nxe2x80x94G or xe2x80x94(C(R6)(R7))pxe2x80x94Mxe2x80x94(R4-heteroaryl);
R2 and R3 are independently selected from the group consisting of H, C1-6 alkyl, xe2x80x94(C(R6)(R7))nxe2x80x94G, xe2x80x94G2 and xe2x80x94S(O)eR13; or R2 and R3, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94N(R19)xe2x80x94;
R4 and R5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, xe2x80x94OR6, xe2x80x94OC(O)R6, xe2x80x94OC(O)N(R6)(R7), xe2x80x94N(R6)(R7), C1-6 alkyl, xe2x80x94CF3, xe2x80x94C2F5, xe2x80x94COR6, xe2x80x94CO2R6, xe2x80x94CON(R6)(R7), xe2x80x94S(O)eR13, xe2x80x94CN, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94NR6CO2R16, xe2x80x94NR6COR7, xe2x80x94NR8CON(R6)(R7), NO2, xe2x80x94N(R6)S(O)2R13 or xe2x80x94S(O)2N(R6)(R7); or adjacent R4 substituents or adjacent R5 substituents can form a xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 group;
R6, R7, R8, R13 and R14 are independently selected from the group consisting of H, C1-6 alkyl, C2-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, R15-phenyl, and R15-benzyl;
R9 is independently selected from the group consisting of R6 and xe2x80x94OR6;
or R6 and R7, or R7 and R9, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94N(R19)xe2x80x94;
R6a, R7a, R8a, R9a, R10 and R10a are independently selected from the group consisting of H and C1-6 alkyl;
R15 is 1 to 3 substituents independently selected from the group consisting of H, xe2x80x94OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogeno, xe2x80x94CF3, xe2x80x94C2F5, xe2x80x94COR10, xe2x80x94CO2R10, xe2x80x94C(O)N(R10)2, xe2x80x94S(O)eR10a, xe2x80x94CN, xe2x80x94N(R10)COR10, xe2x80x94N(R10)CON(R10)2 and xe2x80x94NO2;
R16 is C1-6 alkyl, R15-phenyl or R15-benzyl;
R19 is H, C1-C6 alkyl, xe2x80x94C(O)N(R10)2 or xe2x80x94CO2R10;
n and p are independently 1-6;
G is selected from the group consisting of H, R4-aryl, R4-hetero-cycloalkyl, R4-heteroaryl, R4-cycloalkyl, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OR6, xe2x80x94N(R6)(R7), xe2x80x94COR6, xe2x80x94CO2R6, xe2x80x94CON(R7)(R9), xe2x80x94S(O)eR13, xe2x80x94NR6CO2R16, xe2x80x94NR6COR7, xe2x80x94NR8CON(R6)(R7), xe2x80x94N(R6)S(O)2R13, xe2x80x94N(R6)S(O)2N(R33)(R34), xe2x80x94S(O)2N(R6)(R7), xe2x80x94OC(O)R6, xe2x80x94OC(O)N(R6)(R7), xe2x80x94C(xe2x95x90NOR8)N(R6)(R7), xe2x80x94C(xe2x95x90NR25)N(R6)(R7), xe2x80x94N(R8)C(xe2x95x90NR25)N(R6)(R7), xe2x80x94CN, xe2x80x94C(O)N(R6)OR7, and xe2x80x94C(O)N(R9)xe2x80x94(R4-heteroaryl), provided that when n is 1, G is not xe2x80x94OH or xe2x80x94N(R6)(R7);
M is selected from the group consisting of a double bond, xe2x80x94Oxe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(R6)(OR7)xe2x80x94, xe2x80x94C(R8)(N(R6)(R7))xe2x80x94, xe2x80x94C(xe2x95x90NOR6) N(R7)xe2x80x94, xe2x80x94C(N(R6)(R7))xe2x95x90NOxe2x80x94, xe2x80x94C(xe2x95x90NR25)N(R6)xe2x80x94, xe2x80x94C(O)N(R9)xe2x80x94, xe2x80x94N(R9)C(O)xe2x80x94, xe2x80x94C(xe2x95x90S)N(R9)xe2x80x94, xe2x80x94N(R9)C(xe2x95x90S)xe2x80x94 and xe2x80x94N(R6)C(O)N(R7)xe2x80x94, provided that when n is 1, G is not OH or xe2x80x94NH(R6); and when p is 2-6, M can also be xe2x80x94N(R6)C(xe2x95x90NR25)N(R7)xe2x80x94 or xe2x80x94OC(O)N(R6)xe2x80x94;
G2 is R4-aryl, R4-heterocycloalkyl, R4-heteroaryl, R4-cycloalkyl, xe2x80x94COR6, xe2x80x94CO2R16, xe2x80x94S(O)2N(R6)(R7) or xe2x80x94CON(R6)(R7);
e is 0, 1 or 2, provided that when e is 1 or 2, R13 and R10a are not H;
R25 is H, C1-C6 alkyl, xe2x80x94CN, R15-phenyl or R15-benzyl;
Z is 
g, h and j are independently 0-2;
k is1-4;
X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR9xe2x80x94;
J is xe2x95x90O, xe2x95x90S, xe2x95x90NR9, xe2x95x90NCN or xe2x95x90NOR1;
J1 and J2 are independently selected from the group consisting of two hydrogen atoms, xe2x95x90O, xe2x95x90S, xe2x95x90NR9 and xe2x95x90NOR1;
R26, R27 and R29 are independently selected from the group consisting of H, C1-6 alkyl, xe2x80x94(C(R6)(R7))nxe2x80x94G, xe2x80x94G2, xe2x80x94C(O)xe2x80x94(C(R8)(R9))nxe2x80x94G and xe2x80x94S(O)eR13;
R28 is H, xe2x80x94(C(R6)(R7))txe2x80x94G or xe2x80x94CON(R6)(R7);
t is 0, 1, 2 or 3, provided that when j is 0, t is 1, 2 or 3;
R30 is 1-3 substituents independently selected from the group consisting of H, halogeno, xe2x80x94OR6, xe2x80x94OC(O)R6, xe2x80x94OC(O)N(R6)(R7), xe2x80x94N(R6)(R7), C1-6 alkyl, xe2x80x94CF3, xe2x80x94C2F5, xe2x80x94COR6, xe2x80x94CO2R6, xe2x80x94CON(R6)(R7), xe2x80x94S(O)eR13, xe2x80x94CN, xe2x80x94OCF3, xe2x80x94NR6CO2R16, xe2x80x94NR6COR7, xe2x80x94NR8CON(R6)(R7), NO2, xe2x80x94N(R6)S(O)2R13 or xe2x80x94S(O)2N(R6)(R7); or adjacent R30 substituents can form a xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 group;
R31 is independently selected from the group consisting of H and C1-C6 alkyl;
R32 is independently selected from the group consisting of H, xe2x80x94OH and C1-C6 alkoxy; and
R33 and R34 are independently selected from the group consisting of H, C1-C6 alkyl, R15-phenyl and R15-benzyl.
Preferred are compounds of formula I wherein X is xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, a bond, xe2x80x94NR6xe2x80x94, xe2x80x94S(O)exe2x80x94, xe2x80x94N(R6)C(O)xe2x80x94, xe2x80x94OC(O)NR6 or xe2x80x94C(xe2x95x90NOR1)xe2x80x94. More preferred are compounds of formula I wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94N(R6)C(O)xe2x80x94 or xe2x80x94OC(O)NR6. Additional preferred definitions are: b is 1 or 2 when X is xe2x80x94Oxe2x80x94 or xe2x80x94N(R6)xe2x80x94; b is 0 when X is xe2x80x94N(R6)C(O)xe2x80x94; and d is 1 or 2. T is preferably R4-aryl, with R4-phenyl being more preferred. Also preferred are compounds wherein R6a, R7a, R8a and R9a are independently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen being more preferred. Especially preferred are compounds wherein R8a and R9a are each hydrogen, d and b are each 1, X is xe2x80x94Oxe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94N(R6)C(O)xe2x80x94 or xe2x80x94OC(O)NR6, T is R4-aryl and R4 is two substituents selected from C1-C6 alkyl, halogeno, xe2x80x94CF3 and C1-C6 alkoxy.
Also preferred are compounds of formula I wherein R is hydrogen. Q is preferably R5-phenyl; an especially preferred definition for Q is R5-phenyl, wherein R5 is two halogeno substituents.
Preferred are compounds of formula I wherein A is xe2x95x90Nxe2x80x94OR1. R1 is preferably H, alkyl, xe2x80x94(CH2)nxe2x80x94G, xe2x80x94(CH2)pxe2x80x94Mxe2x80x94(CH2)nxe2x80x94G or xe2x80x94C(O)N(R6)(R7), wherein M is xe2x80x94Oxe2x80x94 or xe2x80x94C(O)N(R9)xe2x80x94 and G is xe2x80x94CO2R6, xe2x80x94OR6, xe2x80x94C(O)N(R7)(R9),xe2x80x94C(xe2x95x90NOR8)N(R6)(R7), xe2x80x94C(O)N(R9)(R4-heteroaryl) or R4-heteroaryl. When A is xe2x95x90Nxe2x80x94N(R2)(R3), R2 and R3 are independently preferably H, C1-C6 alkyl, xe2x80x94(C(R6)(R7))nxe2x80x94G or G2.
Preferred definitions of Z are 
Variables g and h are preferably each 1; J is preferably xe2x95x90O; j is preferably 0; k is preferably 1 or 2; and R28 is preferably H.
A more preferred definition of Z is 
wherein k is preferably 1 or 2.
This invention also relates to the use of a compound of formula I in the treatment of for example respiratory diseases such as chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough, bronchospasm; inflammatory diseases such as arthritis and psoriasis; skin disorders such as atopic dermatitis and contact dermatitis; ophthamalogical disorders such as retinitis, ocular hypertension and cataracts; addictions such as alcohol dependence and stress related disorders; central nervous system conditions such as anxiety, migraine, epilepsy, nociception, emesis, depression, psychosis, schizophrenia, Alzheimer""s disease, AIDs related dementia and Towne""s disease; gastrointestinal disorders such as Crohn""s disease and colitis; bladder disorders; atherosclerosis; fibrosing disorders; and obesity.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to the use of said pharmaceutical composition in the treatment of the mammalian disease states listed above.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched alkyl chains. xe2x80x9cLower alkylxe2x80x9d refers to alkyl chains of 1-6 carbon atoms and, similarly, lower alkoxy refers to alkoxy chains of 1-6 carbon atoms.
xe2x80x9cCycloalkylxe2x80x9d means cyclic alkyl groups having 3 to 6 carbon atoms.
xe2x80x9cArylxe2x80x9d means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl.
xe2x80x9cHalogenoxe2x80x9d refers to fluoro, chloro, bromo or iodo atoms.
xe2x80x9cHeterocycloalkylxe2x80x9d refers to 4- to 6-membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94N(R19)xe2x80x94, with the remaining ring members being carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. R4-heterocycloalkyl refers to such groups wherein substitutable ring carbon atoms have an R4 substituent.
xe2x80x9cHeteroarylxe2x80x9d refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 4 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x95x90, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolinyl, thianaphthenyl and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. All positional isomers are contemplated, e.g., 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. R4-heteroaryl refers to such groups wherein substitutable ring carbon atoms have an R4 substituent.
Where R2 and R3, or R6 and R7 substituents on a nitrogen atom form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and/or sulfur atoms or three adjacent hetero-atoms. Typical rings so formed are morpholinyl, piperazinyl and piperidinyl.
In the above definitions, wherein variables R6, R7, R8, R13, R14, R15, R30, R31 and R32, for example, are said to be independently selected from a group of substituents, we mean that R6, R7, R8, R13, R14, R15, R30, R31 and R32 are independently selected, but also that where an R6, R7, R8, R13, R14, R15, R30 R31 or R32 variable occurs more than once in a molecule, those occurrences are independently selected (e.g., if R is xe2x80x94OR6 wherein R6 is hydrogen, X can be xe2x80x94N(R6)xe2x80x94 wherein R6 is ethyl). Similarly, R4 and R5 can be independently selected from a group of substituents, and where more than one R4 and R5 are present, the substituents are independently selected; those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present.
Compounds of formula I can have at least one asymmetrical carbon atom and all isomers, including diastereomers, enantiomers and rotational isomers, as well as E and Z isomers of the oxime, hydrazone and olefin groups, are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I.
Those skilled in the art will appreciate that for some compounds of formula I, one isomer will show greater pharmacological activity than other isomers.
Compounds of the invention have at least one amino group which can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, tartaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Compounds of formula I can be prepared using methods well known to those skilled in the art, for example by procedures disclosed in U.S. Pat. No. 5,696,267, incorporated herein by reference. The skilled artisan will recognize that other procedures may be applicable, and that the procedure may be suitably modified to prepare other compounds within the scope of formula I.
Compounds of formula I as defined are preferably prepared as shown in the following reaction scheme as disclosed in U.S. Pat. No. 5,696,267. In the reaction scheme, the variables are as defined above 
In step 1, a compound of formula 47A, wherein Q is as defined above, is reacted with a base such as lithium diisopropylamide (LDA), KHMDS or KH in an inert organic solvent such as THF or DME to generate a dianion. An acid chloride, ester or amide of formula 46A, 46B, or 46C is added to give a ketone of formula 48. Preferable reaction temperatures ranges from xe2x88x9278xc2x0 C. to 30xc2x0 C.
Alternatively, compounds of formula 48 can be generated by the reaction of a compound of formula 46, preferably 46C, with a metallated species of formula QCH2Mt where Mt is a metal, such as lithium or MgHal, wherein xe2x80x9cHalxe2x80x9d is halogen. The metallated species QCH2Mt can be generated by conventional procedures, such as treatment compounds of formula QCH2Hal with Mg or by treating QCH3 with an organolithium base. 
In step 2, for compounds wherein R is not hydrogen, the ketone 48 is reacted with a suitable base, such as LDA or KH in an inert organic solvent such as THF. For compounds wherein R is alkyl or hydroxyalkyl, a compound Rxe2x80x94R17xe2x80x3, wherein R17xe2x80x3 is leaving group such as Br, I or triflate is added. For compounds wherein R is OH, an appropriate oxidizing agent such as dimethyldioxirane or Davis reagent is added. Preferable reaction temperatures range from xe2x88x9278xc2x0 to 50xc2x0 C. For compounds of the present invention wherein R is H, the ketone 48 is used directly in Step 3. 
In Step 3, ketone 49 is reacted with a base such as LDA in a solvent such as THF, then an olefin of formula 50 is added, wherein R17xe2x80x3 is as defined above, to give the adduct 51. Preferable reaction temperatures range from xe2x88x9278xc2x0 C. to 60xc2x0 C. 
In step 4, ketone 51 is reacted with HAxe2x80x2, wherein Axe2x80x2 is NHxe2x80x94OR1, in an organic solvent such as pyridine or ethanol at a temperature from 25xc2x0 C. to 150xc2x0 C. to give a compound of formula 52. 
In step 5, a compound of formula 52 is oxidized by ozonolysis to give an aldehyde of formula 53. Suitable organic solvents include EtOAc, CH3OH, ethanol, CH2Cl2 or the like. Preferable reaction temperatures are from xe2x88x9278 to 0xc2x0 C. 
In step 6, an aldehyde of formula 53 is reacted with a compound of formula Zxe2x80x94H, wherein Z is as defined above. The reaction is preferably carried out with a suitably substituted amine (as its acid salt e.g. HCl or maleate or as its free base) and a hydride source such as NaBH3CN or sodium triacetoxyborohydride in a suitable solvent (e.g. CH3OH, CH3CH2OH, or CF3CH2OH for NaBH3CN, or THF, 1,2-dichloroethane, CH3CN or CF3CH2OH for triacetoxyborohydride), with 3A sieves to obtain the desired product. Any suitable temperature can be used with preferable temperatures between 0xc2x0 C. and 25xc2x0 C.
Alternatively, a compound of formula I can be prepared from 51 by the following reaction scheme, wherein the variables are as defined for the cited U.S. patent: 
Compound 51 is oxidized to a compound of formula 54 under conditions similar to those described for step 5 above. The aldehyde of formula 54 is reacted with a compound of formula Zxe2x80x94H in a manner similar to that described in Step 6, and the resultant ketone is then reacted with a compound of the formula HAxe2x80x2 as described above in Step 4 to obtain the compound of formula I.
Starting xe2x80x9cZHxe2x80x9d groups are known or are made by procedures known in the art. See, for example, the following Preparations 3-12.
Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups:
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington""s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation for treatment of asthma, cough, bronchospasm, inflammatory diseases, migraine, nociception, depression, emesis and gastrointestinal disorders may be varied or adjusted from about 1 mg to about 1500 mg, preferably from about 50 mg to about 500 mg, more preferably from about 20 mg to about 200 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 1500 mg/day, in two to four divided doses.
Following are examples of preparing starting materials and compounds of formula I. As used herein, Me is methyl, Bu is butyl, Br is bromo, Ac is acetyl, Et is ethyl and Ph is phenyl. 
Prepared using methods described in U.S. Pat. No. 5,696,267. 
Prepared using methods described in U.S. Pat. No. 5,696,267. 
Step 1: Treat a solution of 1-benzyl-4-amino piperidine (25 g, 0.13 mol) in CH3OH (5 mL) with acrylonitrile (9.6 mL, 0.15 mol) at 23xc2x0 C. Stir for 22 h, and concentrate to yield the crude product.
Step 2: Dissolve the product of Step 1 (31.9 g, 0.13 mol) in CH30OH (1 L) add cobalt (II) chloride (34 g, 0.26 mol) followed by NaBH4 (50 g, 0.13 mol) in several small portion over 45 min at 0xc2x0 C. Allow the resulting suspension to stir for 1.5 h, carefully acidify with 3 N HCl until the color turns pink. Extract the aqueous solution with ether (Et2O) (1 L), add NaOH at 10xc2x0 C. until pH=12. Extract the resulting suspension with Et2O (1 L), then CH2Cl2 (2xc3x971 L). Filter the aqueous layer to remove the solid material, and further extract with CH2Cl2 (3xc3x971 L). Concentrate the combined organic layer to give 23.6 g of the desired product.
Step 3: Dissolve the product of Step 2 (10.0 g, 0.41 mol) in anhydrous tetrahydrofuran (THF) (70 mL), treat with carbonyldiimidazole (13.2 g, 0.81 mol), and heat to 60xc2x0 C. for 14 h. Concentrate the mixture, and filter through a silica plug with CH2Cl2 and CH3OH (sat. with NH3) at a ratio of 94:6 to give 8.6 g of the title product. 
Step 1: Treat a solution of 4-amino-N-benzyl piperidine (20.4 mL, 0.10 mol) in CHCl3 (30 mL) with phthalide anhydride (10.0 g, 0.068 mol) and heat the mixture to reflux at 70xc2x0 C. for 18 h. Add water and CH2Cl2, separate the layers, extract the aqueous layer with CH2Cl2 (2xc3x9740 mL), wash the combined organic layers with brine, concentrate and purify the mixture with column chromatography, eluting with CH2Cl2 and CH3OH (sat. with NH3) at a ratio of 99:1 to give 6.9 g of the desired product.
Step 2: Dissolve the product of Step 1 in acetic acid (HOAc) (10 mL), add zinc dust (1.28 g, 20 mmol) and heat to reflux at 120xc2x0 C. for 12 h. After cooling the mixture, slowly add NaHCO3 (sat.) solution until pH=10, separate the layers, extract the aqueous layer with CH2Cl2 (2xc3x9740 mL), wash the combined organic layers with brine, concentrate the mixture, and purify by column chromatography, eluting with EtOAc:hexane (1:1) with 2% triethylamine (TEA) to give 0.50 g product. 
Treat a solution of 4-amino-N-benzyl piperidine (1.0 g, 5.26 mmol) and 2-acetylbenzoic acid (1.0 g, 6.10 mmol) in dichloroethane (10 mL) with NaBH3CN (0.37 g, 6.0 mmol) and stir at 23xc2x0 C. for 24 h. Heat the mixture to 80xc2x0 C. for an additional 24 h. Add water (30 mL) and EtOAc (30 mL), filter through celite, separate layers of filtrate and concentrate the organic layer. Purify by column chromatography, eluting with EtOAc:hexane (1:2) with 2% TEA to give 0.86 g product. 
Dissolve the product of Preparation 4, Step 1 (0.76 g, 2.38 mmol) in anhydous THF (6 mL) and add CH3MgBr (3 M, 2 mL, 6 mmol) at 0xc2x0 C. Warm the mixture and stir at 23xc2x0 C. for 3 h. Quench with water and CH2Cl2 at 0xc2x0 C., separate the layers, and extract the aqueous layer with CH2Cl2 (2xc3x9740 mL), wash the combined organic layer with brine and concentrate to give 0.68 g product. 
Using procedures known in the art, treat a solution of 3,4-dichloro-phenylacetic acid with N-t-BOC-sarcosine methyl ester and separately treat 2-bromo-ethanol with t-butyldimethylsilylchloride. React the product of the first step with NaH, and add the product of the second step and Nal. Treat the resultant product with O-methoxylamine HCl, followed by deprotection using HCl in CH2Cl2. Chiral material was obtained by chiral separation using HPLC. 
Step 1: Treat a solution of t-butyl-n-(2-aminoethyl)carbamate (18.6 g, 116 mmol) and 1-benzyl-4-piperidone (20 g, 106 mmol) in CH2Cl2 (300 mL) with HOAc (4.1 g, 68 mmol) and sodium triacetoxyborohydride (25 g, 118 mmol) at 0xc2x0 C., and stir for an additional 15 h at 23xc2x0 C. Add NaHCO3 (sat.) (150 mL) and extract with CH2Cl2 (150 mLxc3x972), wash the combined organic layer with brine and concentrate to give 35.5 g product.
Step 2: Dissolve the product of Step 1 (7 g, 21 mmol) and Et3N (6.37 g, 63 mmol) in CH2Cl2 (200 mL), add chloroacetyl chloride (2.85 g, 25 mmol), and stir for 2 h at 23xc2x0 C. Add NaHCO3 solution (150 mL) and extract with CH2Cl2 (150 mLxc3x972), wash the combined organic layer with brine and concentrate. Purify by column chromatography, eluting with CH2Cl2 and CH3OH (sat. with NH3) at a ratio of 97:3 to give 5.3 product.
Step 3: Dissolve the product of Step 2 (5.3 g, 12.0 mmol) in CH2Cl2 with trifluoroacetic acid (15 mL) and stir for 1 h at 23xc2x0 C. Remove the solvent under reduced pressure and dilute with CH2Cl2 and NaOH (1 M) until pH=10. Extract with CH2Cl2 (150 mLxc3x972), wash the combined organic layer with brine, and concentrate to yield 3.3 g of the title compound. 
Step 1: Use a procedure similar to Step 1 of Preparation 8, substituting glycine methyl ester hydrochloride for t-butyl-n-(2-aminoethyl)carbamate and HOAc.
Step 2: Treat the product of Step 1 with Boc-glycine using an amidation procedure similar to Step 1 of Example 7A.
Step 3: Treat the product of Step 2 with trifluoroacetic acid using a procedure similar to Step 3 of Preparation 8 to obtain the title compound. 
Step 1: Dissolve 4-benzyl-piperidone (11.48 g, 50.7 mmol) in EtOH (60 mL), treat with 3-aminopropanol (8.29 g, 110.4 mmol) and stir for 90 min. Cool to 0xc2x0 C. and add HCl in dioxane (14 mL, 56 mmol), followed by NaBH3CN (7.8 g, 124 nmol). Allow the mixture to warm up to 23xc2x0 C., and stir for additional 20 h. Quench with water and dilute with EtOAc, separate the organic layer and basify the aqueous layer until pH greater than 10. Extract the organic layer with EtOAc (2xc3x97100 mL), wash the combined organic layer with brine and concentrate. Purify by column chromatography, eluting with CH2Cl2 and CH3OH (sat. with NH3) at a ratio of 94:6 to give 7.5 g product.
Step 2: Treat the product of step 1 using procedure similar to Preparation 3, Step 3, to give 6.6 g of the title compound. 
To a 5L 3-neck flask equipped with a mechanical stirring apparatus and charged with 1,2 dichloroethane (400 mL), add N-Boc-piperidone (20g, 100 mmol, 1 eq) followed by 3-amino-1-propanol (9.21 mL, 120 mmol, 1.2 eq) and stir for 30 min. Add Na(OAc)3BH (25.4 g, 120 mmol, 1.2 eq) and stir for 4 h. Cool reaction to 0xc2x0 C. and add 300 mL of saturated aqueous NaHCO3. Add p-nitrophenylchloroformate (30.25 g, 150 mmol, 1.5 eq), stir for 90 min and store for 14 h at xe2x88x9220xc2x0 C. Warm to 0xc2x0 C. and check for complete reaction by TLC. Prepare a solution of NaBr (11.3 g, 110 mmol, 1.1 eq in 300 mL of saturated aqueous NaHCO3 (sonicate for 5 min)) and add to the reaction vessel. Add TEMPO (156 mg, 1 mmol). With vigorous stirring, use a 500 mL addition funnel to add 300 mL of commercial bleach (ca 0.7 M, 220 mmol, 2.2 eq). If reaction is not complete as shown by TLC, add bleach in small portions (25 mL) until complete. When TLC shows complete reaction, add saturated aqueous Na2S2O3 (300 mL) and transfer to a separatory funnel. Isolate the organic layer and extract the aqueous layer with CH2Cl2 (2xc3x971 L). Combine the organic layers and wash with saturated aqueous NaHCO3 (1 L). Back extract the last aqueous wash with 1 L CH2Cl2, dry over Na2SO4 and concentrate to give 65 g crude product. Purify by silica gel chromatography using 800 g silica, eluting with hexane/EtOAc gradient elution (2:1 -- greater than 1:1) to obtain 36.5 g (87%) of the desired aldehyde.
Preparation 12A
Step 1
Using a procedure similar to Preparation 11 with phenyl chloroformate in place of 4-nitrophenylchloroformate, prepare the corresponding phenyl carbamate aldehyde.
Step 2
Stir a solution of the product of step 1 (5 g, 13.2 mmol), NH2CH3 (7.3 mL of 2M in THF), in 2,2,2-trifluoroethanol (150 mL) for 30 min, then add 4.67 g of Na(OAc)3BH and stir for 18 h. Filter through a frit, rinse with EtOAc, wash the filtrate with sat NaHCO3 then brine, dry with Na2SO4 and concentrate in vacuo. Dissolve the crude in DMF (100 mL) and heat to 100xc2x0 C. for 1 h. Remove the DMF in vacuo and purify by silica gel chromatography, eluting with EtOAc/CH3OH 9:1 to obtain 2.46 g of the desired boc-piperidine.
Step 3
Dissolve the product of step 2 in 30 mL of CH2Cl2 (30 mL) at 0xc2x0 C. and treat with 50 mL of HCl/dioxane (4N) and stir until no starting material remains by TLC. Concentrate in vacuo and filter the resulting HCl salt through a plug of silica gel, eluting with CH2Cl2/CH3OH (sat with NH3) to obtain the desired piperidine free base.
Preparation 12B
Using a procedure similar to Preparation 12A, substitute isopropylamine for NH2CH3 and heat to 125xc2x0 C. for 6-8 h instead of 100xc2x0 C. for 1 h in step 2.
Preparation 12C-12H
Step 1
Using a procedure similar to that of Preparation 12A, substituting the product of Preparation 11 for the phenyl carbamate in step 1 and using the appropriate amine, the corresponding Boc-piperidines were prepared. For insoluble amines (Prep. 12D) 1-20% Et3N was added to 2,2,2 trifluoroethanol as a co-solvent in step 2. In step 2, hindered amines (Prep. 12H) may require sustained heating (120xc2x0 C., 4-5d) in DMF for cyclization to occur. For less hindered amines, cyclization may be spontaneous and may not require heating in DMF.
Step 2
Deprotect, using a procedure similar to Preparation 12A, step 3.
Preparation 12I-12L
Treat a solution (0.05-0.25 mmol) of the desired Boc protected piperidine obtained from Preparation 12E-12H, step 1, in CH2Cl2 with 1.5-5 eq mCPBA and stir for 2-18 h. Concentrate in vacuo and purify by silica gel chromatography. Deprotect the Boc group using a procedure similar to that of Preparation 12A, step 3, to give the appropriate piperidine.
Preparation 12M
Using a procedure similar to Preparations 12C-H, steps 1 and 2, substituting glycineamide for the appropriate amine, the resulting glycineamide substituted urea/piperidine free base is prepared.
Preparation 12N
Step 1
Treat a solution of the product of Preparation 12A, step 1 (6.2 g, 16.5 mmol) in pyridine (100 mL) with NH2OH (1.72 g, 24.7 mmol) and heat to 60xc2x0 C. for 2.5 h. Cool and concentrate in vacuo and purify by silica gel chromatography, eluting with CH2Cl2/CH3OH (NH3) to obtain 5.9 g (88%) of the oxime as a white powder.
Step 2
Treat a solution of the product of step 1(5.7 g, 15 mmol) in 170 mL CH3OH with a trace amount of methyl orange indicator followed by NaCNBH3 (1.03 g). Add 1M HCl/CH3OH until mixture remains orange (ca. 23 mL). Quench with 400 mL EtOAc and 75 mL sat NaHCO3. Filter the resulting emulsion through celite and wash with EtOAc. Wash organic layers with 75 mL saturated NaHCO3, then brine, dry over Na2SO4 and concentrate in vacuo to obtain 3.82 g (67%) of the hydroxyl amine as a colorless glass.
Step 3
Dissolve the product of step 2 in 50 mL DMF and heat to 100xc2x0 C. for 4 h. Concentrate in vacuo and purify by silica gel chromatography using CH2Cl2/CH3OH (NH3) to obtain 3.0 g (99%) of the hydroxyl urea.
Step 4
In a procedure similar to Preparation 12A, step 3, deprotect the Boc group to obtain the desired piperidine.
Preparation 12O
Step 1
Treat a solution of the product of Preparation 12A, step 1 (3.0 g, 7.13 mmol) in 1,2-dichloroethane (20 mL) with aminomorpholine (1.37 mL, 14.25 mmol) and Na(OAc)3BH (3.0 g). Isolate the resulting hydrazone by filtering the reaction mixture through a frit and concentrating in vacuo.
Step 2
Treat a solution of the product of step 1 in 50 mL THF with 1 eq of tosic acid followed by NaCNBH3 (2 eq). Quench with sat. NaHCO3 and extract with EtOAc. Wash the organic layers with saturated NaHCO3, then brine, dry over Na2SO4 and concentrate in vacuo. Purify by silica gel chromatography, eluting with EtOAc/hexane (2:1) with 2% Et3N to obtain 1.5 g of the desired hydrazone.
Step 3
Dissolve the product of step 2 in 50 mL DMF and heat to 120xc2x0 C. for 3 h. Concentrate in vacuo and purify by silica gel chromatography, eluting with CH2Cl2/CH3OH (NH3) to obtain 255 mg (10%, 2 steps) of the aminomorpholino urea.
Step 4
In a procedure similar to Preparation 12A, step 3, deprotect the Boc group to obtain the desired piperidine.
Preparation 12P
Step 1
Using a procedure similar to Preparation 12A, Step 2, substitute aminoacetonitrile for methyl amine. Dissolve the product in CH3OH, add Raney Ni, and shake the resulting mixture on a Parr shaker at 50 psi of H2 pressure for 3 h. Filter the mixture through celite and concentrate to give the desired product.
Step 2
Dissolve the product of Step 1 (0.17 g, 0.52 mmol) in CH2Cl2 and treat with methyl isocyanate (0.035 ml, 0.57 mmol) at 23xc2x0 C. for 3 h. Dilute with water and CH2Cl2, separate the layers, and extract the aqueous layer with CH2Cl2 (2xc3x9740 ml), wash the combined organic layers with brine and concentrate. Purify by column chromatography using CH2Cl2 and CH3OH (sat. with ammonia) at a ratio of 98:2 to give 0.68 g of product.
Step 3
Use a procedure similar to Preparation 12A, Step 3, to give the desired product.
Preparation 12Q-12T
Using a procedure similar to Preparation 12B, substitute for methyl isocyanate the appropriate isocyante or chloride.
Preparation 12U
Step 1
Dissolve the product form Preparation 12P, Step 1, in dioxane, treat with sulfamide, reflux at 100xc2x0 C. for 8 h, and concentrate to give a crude product.
Step 2
Use a procedure similar to Preparation 12A, Step 3, to give the desired product.